Cellular transformation by human papillomaviruses: lessons learned by comparing high- and low-risk viruses

Abstract

The oncogenic potential of papillomaviruses (PVs) has been appreciated since the 1930s yet the mechanisms of virally-mediated cellular transformation are still being revealed. Reasons for this include: a) the oncoproteins are multifunctional, b) there is an ever-growing list of cellular interacting proteins, c) more than one cellular protein may bind to a given region of the oncoprotein, and d) there is only limited information on the proteins encoded by the corresponding non-oncogenic PVs. The perspective of this review will be to contrast the activities of the viral E6 and E7 proteins encoded by the oncogenic human PVs (termed high-risk HPVs) to those encoded by their non-oncogenic counterparts (termed low-risk HPVs) in an attempt to sort out viral life cycle-related functions from oncogenic functions. The review will emphasize lessons learned from the cell culture studies of the HPVs causing mucosal/genital tract cancers.

Fig. 1

Schematic of the HPV 16 E6 protein. The two zinc binding sites are conserved among the different HPV types. Protein binding regions are shown for HPV 16 E6. The text below the schematic displays the aligned sequences of high-risk HPV 6 E6 and low-risk HPV 16 E6.

Fig. 2

Schematic of the HPV 16 E7 protein. The positions of CR1, CR2, and the zinc binding site, as well as the LXCXE motif and CKII site within CR2 are shown. The zinc binding site is conserved among the different HPV types. Protein binding regions are shown for HPV 16 E7. The text below the schematic displays the aligned sequences of high-risk HPV 6 E7 and HPV 16 E7. The PTLHE (6–10), DLYC (22–26) sequences referred to in the text are underlined; the amino acid conferring low or high Rb binding affinity is italicized; the PKC site in HPV 6 E7 is in purple; the LXCXE motif in red; and the CKII recognition sequence in blue. The proximity of the sequences required for abrogating p21^CIP1 activity (aa 68–70 and 79–83) and for binding HDAC is denoted by underlining and brown lettering, respectively.